JP6095549B2 - Composition containing riboflavin and sesamin - Google Patents
Composition containing riboflavin and sesamin Download PDFInfo
- Publication number
- JP6095549B2 JP6095549B2 JP2013213305A JP2013213305A JP6095549B2 JP 6095549 B2 JP6095549 B2 JP 6095549B2 JP 2013213305 A JP2013213305 A JP 2013213305A JP 2013213305 A JP2013213305 A JP 2013213305A JP 6095549 B2 JP6095549 B2 JP 6095549B2
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- JP
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- Prior art keywords
- sesamin
- riboflavin
- fatigue
- action
- vitamin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- PEYUIKBAABKQKQ-AFHBHXEDSA-N (+)-sesamin Chemical compound C1=C2OCOC2=CC([C@H]2OC[C@H]3[C@@H]2CO[C@@H]3C2=CC=C3OCOC3=C2)=C1 PEYUIKBAABKQKQ-AFHBHXEDSA-N 0.000 title claims description 134
- PEYUIKBAABKQKQ-UHFFFAOYSA-N epiasarinin Natural products C1=C2OCOC2=CC(C2OCC3C2COC3C2=CC=C3OCOC3=C2)=C1 PEYUIKBAABKQKQ-UHFFFAOYSA-N 0.000 title claims description 121
- VRMHCMWQHAXTOR-CMOCDZPBSA-N sesamin Natural products C1=C2OCOC2=CC([C@@H]2OC[C@@]3(C)[C@H](C=4C=C5OCOC5=CC=4)OC[C@]32C)=C1 VRMHCMWQHAXTOR-CMOCDZPBSA-N 0.000 title claims description 110
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 title description 197
- 239000002151 riboflavin Substances 0.000 title description 85
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- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 title description 84
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- KQRXQIPRDKVZPW-ISZNXKAUSA-N sesaminol Chemical compound C1=C2OCOC2=CC([C@H]2OC[C@H]3[C@@H]2CO[C@@H]3C2=CC=3OCOC=3C=C2O)=C1 KQRXQIPRDKVZPW-ISZNXKAUSA-N 0.000 claims description 3
- KQRXQIPRDKVZPW-UHFFFAOYSA-N sesaminol Natural products C1=C2OCOC2=CC(C2OCC3C2COC3C2=CC=3OCOC=3C=C2O)=C1 KQRXQIPRDKVZPW-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- A—HUMAN NECESSITIES
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Description
本発明は、リボフラビンの生理活性を増強しうる組成物で、リボフラビンとセサミン類とを含有する組成物に関し、より詳細には、各種疾患及び外傷に起因する痛みを予防および／または低減させることができる鎮痛作用を有する組成物、あるいは、肉体的および／または精神的疲労を予防および／または軽減させることができる抗疲労作用を有する組成物、およびこれを含有した飲食品に関する。 The present invention relates to a composition that can enhance the physiological activity of riboflavin and contains riboflavin and sesamin, and more specifically, can prevent and / or reduce pain caused by various diseases and trauma. The present invention relates to a composition having an analgesic action, or a composition having an anti-fatigue action capable of preventing and / or reducing physical and / or mental fatigue, and a food and drink containing the same.
リボフラビン（Riboflavin）は、ビタミンＢ2（Vitamin B2）とも呼ばれ、ビタミンの中で水溶性ビタミンに分類される生理活性物質である。このリボフラビンは、白内障を含む多くの眼の疾患の予防や治療に役立ち、眼の充血、乾燥、かゆみ、眼精疲労といった症状を改善することもあるといわれている（フリー百科事典『ウィキペディア(Wikipedia)』：インターネットhttp://ja.wikipedia.org/）。また、リボフラビンの生理活性として、リボフラビン系化合物が免疫機能賦活作用を有すること（特許文献１）や、リボフラビン系化合物がトキシンショック予防治療剤として有用であること（特許文献２）が報告されている。 Riboflavin is also called vitamin B 2 (Vitamin B 2 ), and is a physiologically active substance classified as a water-soluble vitamin among vitamins. Riboflavin is useful for the prevention and treatment of many eye diseases, including cataracts, and is said to improve symptoms such as redness, dryness, itchiness, and eye strain (free encyclopedia Wikipedia ) ”: Internet http://en.wikipedia.org/). Moreover, as a physiological activity of riboflavin, it has been reported that a riboflavin compound has an immune function stimulating action (Patent Document 1) and that a riboflavin compound is useful as a preventive and therapeutic agent for toxin shock (Patent Document 2). .
さらに、リボフラビンの生理活性として鎮痛作用についての報告もある。例えば、リボフラビンを高用量で摂取することにより片頭痛の予防に効果があったこと（非特許文献１）や、炎症系の痛みについて腹腔内に3〜100mg/kgの濃度で投与した場合に用量に依存して鎮痛作用を示すが神経性の痛みについては効果がないこと（非特許文献２）、1〜50mg/kgでの濃度で経口投与した場合にはホルマリンテストでの鎮痛効果は25mgで頭打ちになり、75mgまで増やしても効果は伸びなかったこと等が報告されている（非特許文献２，３）。 In addition, there are reports on analgesic activity as a physiological activity of riboflavin. For example, ingestion of riboflavin at a high dose was effective in preventing migraine (Non-patent Document 1), and when inflammatory pain was administered intraperitoneally at a concentration of 3 to 100 mg / kg It shows analgesic action depending on the drug, but it has no effect on neuropathic pain (Non-patent Document 2). When administered orally at a concentration of 1-50 mg / kg, the analgesic effect in the formalin test is 25 mg. It has been reported that the effect has not increased even if it is increased to 75 mg (Non-patent Documents 2 and 3).
一方、ビタミンＢ2を含むビタミンＢ群の抗疲労作用、すなわちビタミンＢ群の疲労回復及び疲労予防作用が知られている（特許文献３）。また、疲れた時や肌荒れの場合に摂取するためのビタミンＢ1とビタミンＢ2とビタミンＢ6とを含有するサプリメントやドリンク剤が市販されている。 On the other hand, the anti-fatigue action of vitamin B group containing vitamin B 2 , that is, the fatigue recovery and fatigue preventive action of vitamin B group is known (Patent Document 3). In addition, supplements and drinks containing vitamin B 1 , vitamin B 2 and vitamin B 6 to be taken when tired or rough skin are commercially available.
上記のとおり、リボフラビンの生理活性は種々報告されているものの、その効果は必ずしも十分ではなく、リボフラビンは他の化合物の生理活性を補完する目的で配合されるのが主であり、リボフラビン自体の生理活性を増強することは今まで示唆も開示もなされていなかった。また、上記のとおり、ビタミンＢ群の抗疲労作用が知られているが、具体的にリボフラビン（ビタミンＢ2）の抗疲労作用については何ら開示されていなかった。 As described above, although various physiological activities of riboflavin have been reported, the effect is not always sufficient, and riboflavin is mainly formulated for the purpose of complementing the physiological activity of other compounds. Up to now, no activity has been suggested or disclosed. Further, as described above, the anti-fatigue action of the vitamin B group is known, but specifically, no anti-fatigue action of riboflavin (vitamin B 2 ) has been disclosed.
本発明は、ヒトや動物等に対して安全で、したがって、継続摂取が可能であり、かつリボフラビンの生理活性を増強しうる組成物、特に飲食品を提供することを目的とする。 An object of the present invention is to provide a composition, particularly a food or drink, which is safe for humans and animals, and can be continuously ingested, and can enhance the physiological activity of riboflavin.
本発明者らは、上記課題を解決するために鋭意検討を行った結果、驚くべきことに、リボフラビンをセサミン類とともに摂取すると、リボフラビンの生理活性が増強されることを見出した。具体的には、上記のとおり、リボフラビン単独の経口投与による鎮痛作用の効果には上限があるが、セサミン類とともに摂取することによりリボフラビンの効果が増強され、リボフラビン単独摂取では得られない鎮痛効果を奏することを見出した。また、本発明者らは、疲労度を評価するためのモデルとされている水浸負荷モデル動物による遊泳試験を用いて評価した結果、リボフラビンに抗疲労作用があることを見出した。そして、その抗疲労作用がセサミン類を併用することで、リボフラビン単独摂取では得られない作用を奏すること、リボフラビンとセサミン類とが優れた相乗作用を発揮することを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have surprisingly found that when riboflavin is ingested with sesamin, the physiological activity of riboflavin is enhanced. Specifically, as described above, there is an upper limit to the effect of analgesic action by oral administration of riboflavin alone, but the effect of riboflavin is enhanced by ingestion with sesamin, and the analgesic effect that cannot be obtained by ingestion of riboflavin alone. I found out to play. In addition, the present inventors have found that riboflavin has an anti-fatigue action as a result of evaluation using a swimming test using a water immersion load model animal, which is a model for evaluating the degree of fatigue. And the anti-fatigue action is combined with sesamin, it is found that there is an action that can not be obtained by riboflavin alone intake, riboflavin and sesamin exhibit an excellent synergistic effect, to complete the present invention It came.
すなわち、本発明は下記の通りの飲食物を含む組成物に関するものである。
１．リボフラビンと、セサミン類とを含有する組成物。
２．リボフラビンの総量１に対して、セサミン類の総量の割合（重量比）が４．５以下である上記１に記載の組成物。
３．セサミン類が、セサミン類を１重量％以上含有する、セサミン類濃縮物である上記１または２に記載の組成物。
４．セサミン類が、セサミンおよび／またはエピセサミンである上記１〜３のいずれかに記載の組成物。
５．リボフラビンが、リン酸リボフラビンナトリウムまたは酪酸リボフラビンのいずれかである上記１〜４のいずれかに記載の組成物。
６．経口用である上記１〜５のいずれかに記載の組成物。
７．リボフラビンと、セサミン類とを有効成分として含有する鎮痛剤。
８．リボフラビンを有効成分として含有する抗疲労剤。
９．リボフラビンと、セサミン類とを有効成分として含有する抗疲労剤。
１０．リボフラビンの生理活性を向上させるための、セサミン類の使用。
That is, this invention relates to the composition containing the following food and drink.
1. A composition containing riboflavin and sesamin.
2. 2. The composition according to 1 above, wherein the ratio of the total amount of sesamins (weight ratio) to the total amount of riboflavin 1 is 4.5 or less.
3. 3. The composition according to 1 or 2 above, wherein the sesamin is a sesamin concentrate containing 1% by weight or more of the sesamin.
4). 4. The composition according to any one of 1 to 3 above, wherein the sesamin is sesamin and / or episesamin.
5. 5. The composition according to any one of 1 to 4 above, wherein the riboflavin is either riboflavin sodium phosphate or riboflavin butyrate.
6). 6. The composition according to any one of 1 to 5 above, which is for oral use.
7). An analgesic containing riboflavin and sesamin as active ingredients.
8). An anti-fatigue agent containing riboflavin as an active ingredient.
9. An anti-fatigue agent containing riboflavin and sesamin as active ingredients.
10. Use of sesamin to improve physiological activity of riboflavin.
（リボフラビン）
本発明のリボフラビン（本明細書中、「ビタミンＢ2」と表記することもある）とは、リボフラビン誘導体、またはこれらの薬理学的に許容される塩を含む。ここで、リボフラビン誘導体またはその薬理学的に許容される塩としては、具体的には、フラビンモノヌクレオチド（ＦＭＮ）、フラビンアデニンジヌクレオチド（ＦＡＤ）、リボフラビンテトラブチレイト、リン酸リボフラビンナトリウム（ビタミンＢ2リン酸エステル）、リン酸リボフラビンのモノジエタノールアミン塩、酪酸リボフラビン（ビタミンＢ2酪酸エステル）、ロイコフラビン、モノハイドロフラビン、ロイコフラビンリン酸エステル、ロイコフラビンモノヌクレオチド、又はロイコフラビンアデニンジヌクレオチド等を挙げることができるが、中でも、吸収性が高いリン酸リボフラビンナトリウムや、安定性の優れた酪酸リボフラビンが好適に用いられる。本発明においては、前記のリボフラビンのうちいずれか単独あるいは複数を用いることができる。また、これらはその製造方法に何ら限定されず、天然抽出品、微生物発酵品、合成品のいずれをも用いることができる。
(Riboflavin)
The riboflavin of the present invention (sometimes referred to herein as “vitamin B 2 ”) includes riboflavin derivatives or pharmacologically acceptable salts thereof. Specific examples of the riboflavin derivative or a pharmacologically acceptable salt thereof include flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), riboflavin tetrabutyrate, riboflavin sodium phosphate (vitamin B) 2- phosphate ester), monodiethanolamine salt of riboflavin phosphate, riboflavin butyrate (vitamin B 2- butyrate ester), leucoflavin, monohydroflavin, leucoflavin phosphate ester, leucoflavin mononucleotide, leucoflavin adenine dinucleotide, etc. Among them, phosphoflavin sodium phosphate having high absorbability and riboflavin butyrate having excellent stability are preferably used. In the present invention, any one or more of the above riboflavins can be used. Moreover, these are not limited to the manufacturing method at all, and any of a natural extract, a microbial fermentation product, and a synthetic product can be used.
（セサミン類）
本発明のセサミン類とは、セサミン及びその類縁体を含む。前記のセサミン類縁体としては、エピセサミンの他、例えば特開平４−９３３１号公報に記載されたジオキサビシクロ〔３．３．０〕オクタン誘導体がある。セサミン類の具体例としては、セサミン、セサミノール、エピセサミノール、セサモリン等を例示でき、これらの立体異性体又はラセミ体を単独で、または混合して使用することができるが、本発明においては、セサミン及び／又はエピセサミンを好適に用いることができる。また、セサミン類の代謝体（例えば、特開２００１−１３９５７９号公報に記載）も、本発明の効果を示す限り、本発明のセサミン類に含まれるセサミン類縁体であり、本発明に使用することができる。
(Sesamin)
The sesamin of the present invention includes sesamin and its analogs. Examples of the sesamin analog include episesamin and dioxabicyclo [3.3.0] octane derivatives described in JP-A-4-9331. Specific examples of sesamin can include sesamin, sesaminol, episesaminol, sesamorin and the like, and these stereoisomers or racemates can be used alone or in combination, but in the present invention, , Sesamin and / or episesamin can be suitably used. In addition, metabolites of sesamin compounds (for example, described in JP-A-2001-139579) are sesamin analogs included in the sesamin compounds of the present invention as long as the effects of the present invention are exhibited, and are used in the present invention. Can do.
本発明に用いるセサミン類は、その形態や製造方法等によって、何ら制限されるものではない。例えば、セサミン類としてセサミンを選択した場合には、通常、ごま油から公知の方法（例えば、特開平４−９３３１号公報に記載された方法）によって抽出したセサミン（セサミン抽出物または精製物という）を用いることもできるが、市販のごま油（液状）をそのまま用いることもできる。しかしながら、ごま油を用いた場合には、ごま油特有の風味が官能的に好ましくないと評価されることもあることから、ごま油から抽出された無味無臭であるセサミン抽出物（又はセサミン精製物）を用いることが好ましい。また、ごま油を用いた場合、セサミン含有量が低いため、好ましい量のセサミンを配合しようとすると、処方されるリボフラビン（ビタミンＢ2）含有組成物の単位投与当りの体積が大きくなり過ぎるため、摂取に不都合を生じることがある。特に、経口投与用に製剤化した場合は、製剤（錠剤、カプセルなど）が大きくなり過ぎて摂取に支障が生じる。したがって、摂取量が少なくてよいという観点からもごま油からのセサミン抽出物（又はセサミン精製物）を用いることが好ましい。 The sesamin used for this invention is not restrict | limited at all by the form, manufacturing method, etc. For example, when sesamin is selected as the sesamin, usually sesamin extracted from sesame oil by a known method (for example, the method described in JP-A-4-9331) (referred to as sesamin extract or purified product) Although it can also be used, commercially available sesame oil (liquid form) can also be used as it is. However, when sesame oil is used, the flavor unique to sesame oil may be evaluated as sensory unfavorable, so a tasteless and odorless sesamin extract (or purified sesamin product) extracted from sesame oil is used. It is preferable. In addition, when sesame oil is used, since the sesamin content is low, when trying to formulate a preferable amount of sesamin, the volume per unit dose of the prescribed riboflavin (vitamin B 2 ) -containing composition becomes too large. May cause inconvenience. In particular, when formulated for oral administration, the dosage form (tablets, capsules, etc.) becomes too large, which causes problems in ingestion. Therefore, it is preferable to use a sesamin extract (or a sesamin purified product) from sesame oil from the viewpoint that the intake may be small.
このように、セサミン類としてはセサミン類の濃縮物を用いるのが好ましい。濃縮の度合いは、用いるセサミン類の種類や配合する組成物の形態により適宜設定すればよいが、通常、セサミン類が１重量％以上となるように濃縮されたセサミン類濃縮物を用いるのが好ましい。セサミン類濃縮物中のセサミン類含量は、２０重量％以上がより好ましく、さらに５０重量％以上が好ましく、さらにまた７０重量％以上が好ましく、９０重量％以上まで濃縮（精製）されたものが最適である。 Thus, it is preferable to use a concentrate of sesamin as sesamin. The degree of concentration may be appropriately set depending on the type of sesamin used and the form of the composition to be blended, but it is usually preferable to use a sesamin concentrate concentrated so that the sesamin content is 1% by weight or more. . The sesamin content in the sesamin concentrate is preferably 20% by weight or more, more preferably 50% by weight or more, still more preferably 70% by weight or more, and most preferably concentrated (purified) to 90% by weight or more. It is.
本発明で使用するセサミン類は、上記のとおり、従来の食品中より見出した化合物又はその類縁化合物であるので安全性の面からも優れているのは明らかである。これはまた、７週令のICR雄性マウスに対し、セサミン2.14g/day/kgを２週間連投（経口投与）したところ、何ら異常な症状は認められなかったことからも明らかである。 As described above, since the sesamin used in the present invention is a compound found in conventional foods or a similar compound thereof, it is clear that it is excellent in terms of safety. This is also clear from the fact that sesamin 2.14 g / day / kg was continuously administered (oral administration) for 2 weeks to 7-week-old ICR male mice, and no abnormal symptoms were observed.
本発明で使用するセサミン類、特にセサミン及び／又はエピセサミンについて、本出願人らによって自律神経調節作用を有することが見出されている（国際公開ＷＯ２００４／１０５７４９）が、本発明の鎮痛作用を増強する作用や抗疲労作用を示すことは何ら知られておらず、リボフラビンの生理活性を増強させることについては開示も示唆もされていなかったものである。 The sesamin used in the present invention, particularly sesamin and / or episesamin, has been found by the present applicants to have an autonomic nerve regulating action (International Publication WO2004 / 105749), which enhances the analgesic action of the present invention. It is not known at all that it exhibits an action and an anti-fatigue action, and it has not been disclosed or suggested to enhance the physiological activity of riboflavin.
（鎮痛作用及び剤）
本発明は、ヒトや動物、特にヒトの痛みを予防および／または低減させる鎮痛剤として有用なものである。ここで、動物とは、産業動物、ペットおよび実験動物を表し、具体的には、産業動物とは、ウシ、ウマ、ブタ、ヤギ、ヒツジ等の家畜、ニワトリ、アヒル、ウズラ、七面鳥、ダチョウ等の家禽、ブリ、ハマチ、マダイ、マアジ、コイ、ニジマス、ウナギ等の魚類など産業上飼養することが必要とされている動物をいい、ペットとはイヌ、ネコ、マーモセット、小鳥、ハムスター、金魚などのいわゆる愛玩動物、コンパニオン・アニマルをいい、実験動物とはマウス、ラット、モルモット、ビーグル犬、ミニブタ、アカゲザル、カニクイザルなど医学、生物学、農学、薬学等の分野で研究に供用される動物を表す。
(Analgesic action and agent)
The present invention is useful as an analgesic for preventing and / or reducing pain in humans and animals, particularly humans. Here, animals represent industrial animals, pets, and laboratory animals. Specifically, industrial animals include domestic animals such as cows, horses, pigs, goats, sheep, chickens, ducks, quails, turkeys, ostriches, etc. Animals that are required to be kept in the industry such as Japanese poultry, yellowtail, yellowtail, red sea bream, common horse mackerel, carp, rainbow trout, eel, etc. Pets are dogs, cats, marmoset, small birds, hamsters, goldfish, etc. The so-called companion animal of this animal is a companion animal, and experimental animals represent mice, rats, guinea pigs, beagle dogs, minipigs, rhesus monkeys, cynomolgus monkeys, and other animals used for research in the fields of medicine, biology, agriculture, pharmacy, etc. .
本発明の鎮痛剤は、一過性の軽度の痛みから慢性的で堪え難い程度の激痛までをも対象とする。痛みに対しては、通常、鎮痛剤を用いることにより痛みをコントロールするが、その効果は必ずしも十分ではなく、関節痛、神経痛、腰痛などの慢性的な痛み（疼痛）に対しては、一時的に痛みを治めるに過ぎないばかりか、鎮痛剤の継続的な服用により、胃腸障害、腎臓障害や肝臓障害等の副作用が問題となることも多い。また、この関節痛、神経痛、腰痛などの痛みは、加齢と共に増加する傾向にあることから、近年の急速な高齢化に伴い、単に痛みの改善除去だけでなく、その予防に対する社会的需要も高まっている。 The analgesic agent of the present invention covers a range from transient mild pain to chronic unbearable severe pain. For pain, pain is usually controlled by using an analgesic, but the effect is not always sufficient. For chronic pain (pain) such as joint pain, neuralgia, and back pain, it is temporary. In addition to only relieving pain, side effects such as gastrointestinal disorders, kidney disorders, and liver disorders often become problems due to continuous use of analgesics. In addition, since pains such as joint pain, neuralgia, and back pain tend to increase with aging, with the rapid aging in recent years, not only the improvement and removal of pain but also the social demand for its prevention. It is growing.
本発明の鎮痛剤は、上記の種々の痛みやこれら痛みを伴う疾患に対して有用なものである。本発明の鎮痛剤は、セサミン類を併用することによりリボフラビンの鎮痛作用を相乗的に増強させたものであり、従来の鎮痛剤と比べて優れた鎮痛作用を発揮する。また、長年飲食品として摂取されてきたリボフラビンとセサミン類とを有効成分とするものであり、副作用がなく、継続摂取可能なものである。したがって、日常的に摂取して慢性的な痛みの低減を図ることができるばかりでなく、痛みを伴う疾患（月経痛など）を予防することもできるものであり、新しいタイプの鎮痛剤である。このことは、痛みの感覚が、感受性の強い人と弱い人とで違いがあり、客観的な尺度がなく、正常であるのか病気であるのか明確に判定できない場合も多く、従来の鎮痛剤のような薬剤投与による治療行為としてではなく、日常的に摂取可能な飲食品の形態が望まれていたという事情を鑑みても有用なものであるといえる。 The analgesic of the present invention is useful for the above various pains and diseases accompanied by these pains. The analgesic of the present invention synergistically enhances the analgesic action of riboflavin by using sesamin in combination, and exhibits an excellent analgesic action as compared with conventional analgesics. In addition, riboflavin and sesamin, which have been ingested as food and drink for many years, are active ingredients and can be continuously ingested without side effects. Therefore, it is a new type of analgesic that can be taken daily and can reduce chronic pain, as well as prevent painful diseases (such as menstrual pain). This is because there is a difference in the sense of pain between sensitive and weak people, there is no objective measure, and it is often impossible to clearly determine whether it is normal or ill. It can be said that it is useful not only as a therapeutic action by such drug administration but also in view of the fact that a form of food and drink that can be taken on a daily basis is desired.
（抗疲労作用及び剤）
本発明の組成物は、上記の鎮痛作用のほか、ヒトや動物の抗疲労剤としても有用なものである。ここで、動物とは、上記鎮痛剤の対象となる動物をいうが、中でも本発明の抗疲労剤は、疲労を知覚するヒト、産業動物、ペットおよび実験動物に用いられ、特にヒトに対して好適に用いられる。ここで、産業動物とは、ウシ、ウマ、ブタ、ヤギ、ヒツジ等の家畜や競争馬、猟犬等を、ペットとはイヌ、ネコ等を、実験動物とはマウス、ラット、モルモット、ビーグル犬、ミニブタ、アカゲザル、カニクイザルなど医学、生物学、農学、薬学等の分野で研究に供用される動物を表す。
(Anti-fatigue action and agent)
The composition of the present invention is useful as an anti-fatigue agent for humans and animals in addition to the above analgesic action. Here, an animal refers to an animal that is a target of the above-mentioned analgesic agent. Among them, the anti-fatigue agent of the present invention is used for humans, industrial animals, pets, and laboratory animals that perceive fatigue, particularly for humans. Preferably used. Here, industrial animals are domestic animals such as cattle, horses, pigs, goats, sheep, etc., competitive horses, hounds, etc., pets are dogs, cats, etc., laboratory animals are mice, rats, guinea pigs, beagle dogs, Represents animals used for research in the fields of medicine, biology, agriculture, pharmacy, etc., such as minipigs, rhesus monkeys, and cynomolgus monkeys.
疲労とは、身体的あるいは精神的負荷を連続して与えたときにみられる一時的な身体的および精神的パフォーマンスの低下現象であり、パフォーマンスの低下は、身体的および精神的作業能力の質的あるいは量的な低下を意味する。また、本発明の「疲労」には、慢性疲労症候群や過労死をも包含するものとする。 Fatigue is a temporary decline in physical and mental performance that occurs when physical or mental loads are continuously applied. Or it means the quantitative fall. Further, “fatigue” in the present invention includes chronic fatigue syndrome and death from overwork.
本発明の抗疲労剤とは、上記疲労を減弱させる作用や疲労を回復させる作用をいい、具体的には、運動や作用した部位（脳を含む）の働きの持続時間を向上させること、および同じ運動量や作用量での疲労物質の増加を抑制すること（持久力向上・体力増強）、運動や作用した部位が疲労していないにもかかわらず脳や神経などが疲労感知状態になっていることを改善すること、ならびに運動や作用した部位の疲労状態を通常状態に回復することを促進する効果をいう。 The anti-fatigue agent of the present invention refers to the above-mentioned action to reduce fatigue and the action to recover fatigue, specifically, to improve the duration of exercise and the action of the affected part (including the brain), and Suppress the increase of fatigue substances with the same amount of exercise and action (improve endurance and physical strength), and the brain and nerves are in a fatigue-sensing state even though the part where exercise or action is not fatigued This refers to the effect of promoting the recovery of the fatigue state of the part where the exercise or the action has been performed to the normal state.
また、本発明の抗疲労剤が目的とする慢性疲労症候群とは、日常生活に支障を来すほどの長期的な全身疲労感、倦怠感、微熱、リンパ節腫脹、筋肉痛、関節痛、精神神経症状などの基本的な症状を意味する。本発明の抗疲労剤は、この慢性疲労症候群を処理、すなわち慢性疲労症候群の各症状を緩和し、正常な状態に移行させることができる。さらに、本発明の抗疲労剤が目的とする過労死とは、重度の過労状態にあり、身体的活力を保つことができないにも関わらず、疲労を十分に感じることができなくなり、その結果、脳血管疾患や心疾患を発症して永久的労働不能や死亡に至った状態を意味する。本発明の抗疲労剤は、慢性疲労症候群を処置することができ、それにより過労死を予防しうるものである。 The chronic fatigue syndrome targeted by the anti-fatigue agent of the present invention is long-term general fatigue, fatigue, slight fever, lymphadenopathy, muscle pain, joint pain, mental Means basic symptoms such as neurological symptoms. The anti-fatigue agent of the present invention can treat this chronic fatigue syndrome, that is, alleviate each symptom of chronic fatigue syndrome, and shift it to a normal state. Furthermore, overwork death intended by the anti-fatigue agent of the present invention is a severe overwork state, and despite being unable to maintain physical vitality, fatigue cannot be fully felt, and as a result, It means a condition where cerebrovascular disease or heart disease has developed, resulting in permanent inability to work or death. The anti-fatigue agent of the present invention can treat chronic fatigue syndrome, thereby preventing overwork death.
本発明の抗疲労作用、すなわち「抗疲労剤」としての効果は、例えば次の試験により確認することができる。すなわち、水浸断眠試験における遊泳時間の測定である。水浸飼育のように、十分な睡眠や休息姿勢をとることができず、肉体的にも精神的にも休息できない環境で飼育されたマウスを用い、おもりを負荷させた状態で遊泳させ、１０秒以上鼻が水没してしまうまでの時間を測定することにより、その疲労度を確認するものである。この動物モデルは肉体的及び精神的疲労モデルであるから、被験物質を投与することにより遊泳時間が延長されれば、肉体的及び精神的疲労やそれに伴う筋肉痛等の苦痛を予防または改善できたこと、体力が増強され疲労困憊に至るまでの時間が延長されたこと、疲労状態のもとで身体的活力が維持されたこと等、疲労に対する抵抗性があることが確認される。 The anti-fatigue action of the present invention, that is, the effect as an “anti-fatigue agent” can be confirmed, for example, by the following test. That is, it is a measurement of swimming time in a water immersion sleep sleep test. Using a mouse raised in an environment where it is not possible to take sufficient sleep or resting posture, such as underwater breeding, and where it cannot physically and mentally rest, it is allowed to swim with a weight loaded, 10 The fatigue level is confirmed by measuring the time until the nose is submerged for more than a second. Since this animal model is a physical and mental fatigue model, if the swimming time was extended by administering the test substance, physical and mental fatigue and associated pain such as muscle pain could be prevented or improved. In addition, it is confirmed that there is resistance to fatigue, such as that the time until physical strength is increased and fatigue distress is extended, and that physical vitality is maintained under a fatigue state.
本発明の抗疲労剤は、これを摂取することにより疲れにくくなり、また疲労回復にも効果がある。すなわち、スポーツなどの筋肉運動に際して肉体疲労を感じたとき、計算作業等の連続作業に際して精神疲労を感じたときに摂取して疲労の回復を図ることができることはいうまでもないが、予め摂取してから労働、スポーツなどを行うと疲労を予防することもできる。また、スポーツを行う前や途中で摂取することにより、持久力向上が期待できる。さらに、日常的に摂取することにより、精神的な疲労やそれに伴う疾患をも予防することができる。 The anti-fatigue agent of the present invention is less fatigued when ingested, and is effective in recovering from fatigue. In other words, when you feel physical fatigue during muscular exercise such as sports, you can take it when you feel mental fatigue during continuous work such as calculation work, but you can take it in advance. It is also possible to prevent fatigue when working and playing sports. In addition, endurance can be expected by taking it before or during sports. Furthermore, mental fatigue and associated diseases can be prevented by daily intake.
（リボフラビンとセサミン類とを含有する組成物）
本発明は、リボフラビンにセサミン類を含有させることにより、リボフラビンの生理活性、例えば鎮痛作用や抗疲労作用を相乗的に増強させるとともに、健康食品として利用することで、それぞれの成分の生理作用により、健康増進を図ることができる。
(Composition containing riboflavin and sesamin)
The present invention synergistically enhances the physiological activity of riboflavin, such as analgesic action and anti-fatigue action, by containing sesamins in riboflavin, and by using it as a health food, the physiological action of each component, Can promote health.
本発明のリボフラビンとセサミン類とを含有する組成物においては、それぞれの生理作用を期待するのであればその配合量に制限はない。通常、リボフラビンは、厚生労働省の定める日本人の栄養所要量となるように配合するのがよく、具体的には、１日当たり成人男子1.2mg、成人女子1.0mgである。また、リボフラビンは健康障害を引き起こす最大上限に関する報告がないことから、その配合量に上限はないが、通常、成人１日当たり100mg以下、好ましくは50mg以下程度である。また、セサミン類は、通常、成人１日当たり1〜200mg、好ましくは5〜100mg程度となるように配合する。 In the composition containing the riboflavin and sesamin of the present invention, the blending amount is not limited as long as each physiological action is expected. In general, riboflavin should be formulated so as to meet the nutritional requirements of the Japanese specified by the Ministry of Health, Labor and Welfare. Specifically, it is 1.2 mg adult male and 1.0 mg adult female per day. Moreover, since there is no report on the maximum upper limit causing ill health, riboflavin has no upper limit, but is usually about 100 mg or less, preferably about 50 mg or less per day for an adult. Moreover, sesamin is normally mix | blended so that it may become 1-200 mg per adult, Preferably it is about 5-100 mg.
一方、リボフラビンの生理活性を増強させることを期待して、リボフラビンにセサミン類を配合するのであれば、リボフラビンとして換算（本明細書中、「リボフラビン当量」と表記することもある）した場合に、リボフラビンの総量１に対して、セサミン類の総量の割合を重量比で４．５以下、好ましくは４．０以下、さらに好ましくは３．５以下となるように配合する。配合するセサミン類の割合が多いほどリボフラビンの作用が増強されると予想されるが、上記の割合の範囲内でないと、優れた相乗効果が得られない。配合するセサミン類の下限値は、求める作用、例えば鎮痛作用や抗疲労作用の相乗効果が得られる量であれば制限されず、上記の日用量を参考として配合すればよい。一般的には、リボフラビンとして換算した場合に、リボフラビンの総量１に対して、セサミン類の総量の割合を重量比で０．０１以上、好ましくは０．５以上、より好ましくは０．１以上、さらに好ましくは１以上である。 On the other hand, in the case of blending sesamin with riboflavin in the hope of enhancing the physiological activity of riboflavin, when converted to riboflavin (in this specification, sometimes referred to as “riboflavin equivalent”), The ratio of the total amount of sesamins to the total amount of riboflavin 1 is 4.5 or less, preferably 4.0 or less, more preferably 3.5 or less. It is expected that the action of riboflavin is enhanced as the proportion of sesamin to be blended is increased, but an excellent synergistic effect cannot be obtained unless the proportion is within the above range. The lower limit value of the sesamin to be blended is not limited as long as it is an amount that can provide the desired action, for example, a synergistic effect of analgesic action or anti-fatigue action, and may be blended with reference to the above daily dose. Generally, when converted as riboflavin, the ratio of the total amount of sesamins to the total amount of riboflavin 1 is 0.01 or more, preferably 0.5 or more, more preferably 0.1 or more, More preferably, it is 1 or more.
リボフラビンの生理活性の一つである鎮痛作用において、リボフラビン当量で３０ｍｇのリン酸リボフラビンナトリウムと、５０ｍｇまたは１００ｍｇのセサミン類とを経口摂取した場合、すなわち重量比でリボフラビン：セサミン＝１：１．６７または１：３．３３の場合において、リン酸リボフラビンナトリウムの鎮痛作用が向上することが確認されている（実施例１、２）。また、本発明者らが確認したリボフラビンの生理活性の一つである抗疲労作用において、リボフラビン当量で２５ｍｇまたは５０ｍｇのリン酸リボフラビンナトリウムと、５０ｍｇのセサミン類とを経口摂取した場合、すなわち重量比でリボフラビン：セサミン類＝１：２または１：１の場合において、リン酸リボフラビンナトリウムの抗疲労作用が向上することが、リボフラビン当量で１０ｍｇのリン酸リボフラビンナトリウムと、５０ｍｇのセサミン類とを経口摂取した場合、すなわち重量比でリボフラビン：セサミン類＝１：５の場合には、リン酸リボフラビンナトリウムの抗疲労作用を増強しないことが確認されている（実施例３、４）。 In the analgesic action, which is one of the physiological activities of riboflavin, when 30 mg of riboflavin sodium phosphate and 50 mg or 100 mg of sesamin are orally ingested in a riboflavin equivalent, that is, riboflavin: sesamin = 1: 1.67 by weight ratio. Alternatively, in the case of 1: 3.33, it has been confirmed that the analgesic action of riboflavin sodium phosphate is improved (Examples 1 and 2). Further, in the anti-fatigue action, which is one of the physiological activities of riboflavin confirmed by the present inventors, when riboflavin equivalent of 25 mg or 50 mg of riboflavin sodium phosphate and 50 mg of sesamin are orally ingested, that is, weight ratio In the case of riboflavin: sesamin = 1: 2 or 1: 1, the anti-fatigue action of riboflavin sodium phosphate is improved, and 10 mg riboflavin sodium phosphate and 50 mg sesamin are orally ingested in terms of riboflavin equivalent In other words, when riboflavin: sesamins = 1: 5 by weight ratio, it has been confirmed that the anti-fatigue action of riboflavin sodium phosphate is not enhanced (Examples 3 and 4).
本発明の組成物を医薬組成物として利用する場合、その投与形態は、液剤、錠剤、顆粒剤、散剤、カプセル剤、ドライシロップ剤、丸剤等の形態で経口投与してもよいし、注射剤等の形態で投与してもよく、その形態は、病態やその進行状況、その他の条件によって適宜選択することができる。また、本発明の有効成分であるリボフラビン（酪酸リボフラビンを除く）は水溶性であり、セサミン類は脂溶性であることから、それぞれを別の形態で摂取しても良い。具体的にはリボフラビンの顆粒を水とともに摂取すると同時に、セサミン類を油脂に溶解させて充填したソフトカプセルを摂取する方法や、それぞれ吸収速度に応じて時間差を設けて摂取する方法等により、鎮痛作用を得ることができる。 When the composition of the present invention is used as a pharmaceutical composition, its administration form may be orally administered in the form of solution, tablet, granule, powder, capsule, dry syrup, pill, etc., or injection The form may be appropriately selected depending on the disease state, its progress, and other conditions. Moreover, since riboflavin (excluding riboflavin butyrate) which is an active ingredient of the present invention is water-soluble and sesamin is fat-soluble, each may be ingested in another form. Specifically, by taking the riboflavin granules together with water, at the same time, ingesting soft capsules filled with sesamin dissolved in oil and fat, and taking in a time difference depending on the absorption rate, etc. Can be obtained.
また、本発明の組成物の投与量についても、対象、病態やその進行状況、その他投与形態等の条件によって適宜選択すればよいが、ヒト（成人）を対象に鎮痛作用および／または抗疲労作用を得ることを目的として経口投与する場合には、一般に、１〜２００mg、好ましくは２〜１００mg程度を、１日に１〜３回程度の頻度で連続投与するとよい。 In addition, the dose of the composition of the present invention may be appropriately selected depending on conditions such as the subject, pathological condition and its progress, and other administration forms, but it is analgesic and / or anti-fatigue for humans (adults). In the case of oral administration for the purpose of obtaining the above, generally 1 to 200 mg, preferably about 2 to 100 mg, may be continuously administered at a frequency of about 1 to 3 times a day.
本発明においては、その効果を損なわない限り、リボフラビンとセサミン類との他に、任意の所望成分を配合することができる。例えば、ビタミンＥ、ビタミンＣ等のビタミン類、ミネラル類、ホルモン、栄養成分、香料などの生理活性成分のほか、製剤化において配合される乳化剤、緊張化剤（等張化剤）、緩衝剤、溶解補助剤、防腐剤、安定化剤、抗酸化剤等を適宜配合することができる。本発明の組成物は、上記のとおり、鎮痛剤および／または抗疲労剤として利用可能なものであるが、リボフラビン（ビタミンＢ2）とセサミン類の持つその他の種々の生理作用が相加的に、または相乗的に発揮され得ると考えられることから、上記の医薬組成物と利用されるばかりでなく、健康食品としても好適に利用できる。 In the present invention, any desired component can be blended in addition to riboflavin and sesamin as long as the effect is not impaired. For example, vitamins such as vitamin E and vitamin C, minerals, hormones, nutritional ingredients, physiologically active ingredients such as fragrances, emulsifiers, tonicity agents (isotonic agents), buffers, Solubilizing agents, preservatives, stabilizers, antioxidants and the like can be appropriately blended. As described above, the composition of the present invention can be used as an analgesic and / or an anti-fatigue agent, but in addition to the various other physiological functions of riboflavin (vitamin B 2 ) and sesamins, In addition, since it can be exhibited synergistically, it can be suitably used not only as the above pharmaceutical composition but also as a health food.
ここでいう健康食品とは、例えばカプセル剤や錠剤のように、本発明のリボフラビンとセサミン類とを含有する組成物そのものを有効成分とする製剤又は食品、ならびに一般の食品に上記本発明組成物を１つの成分として配合して、生体に対する鎮痛作用や抗疲労作用等の種々の機能をその食品に付加してなる機能性食品（特定保健用食品や条件付き特定保健用食品が含まれる）を挙げることができる。さらに、生体の痛を予防ないし低減するために用いられる旨や、生体の疲労を軽減または疲労回復を促進する旨の表示を付してなる、鎮痛作用および／または抗疲労作用を有することを特徴とする食品等も包含するものとする。 The health food here refers to, for example, a preparation or food containing the composition itself containing the riboflavin and sesamin of the present invention as an active ingredient, such as capsules and tablets, and the composition of the present invention in general foods. As a single component, functional foods (including special health foods and conditional special health foods) that are added to the food with various functions such as analgesic action and anti-fatigue action on the body Can be mentioned. Furthermore, it has an analgesic action and / or an anti-fatigue action, which is used to prevent or reduce pain in the living body, and has an indication that the fatigue of the living body is reduced or that fatigue recovery is promoted. It also includes foods.
リボフラビンとセサミン類とを含有する健康食品としては、その形態を特に制限するものではなく、例えば、粉末状、顆粒状、錠剤状などの固体状；溶液状、乳液状、分散液状等の液状；またはペースト状等の半固体状などの、任意の形態に調製することができる。 The form of the health food containing riboflavin and sesamin is not particularly limited. For example, it is a solid such as powder, granule, or tablet; a liquid such as solution, emulsion, or dispersion; Or it can prepare in arbitrary forms, such as semi-solid forms, such as paste form.
以下、試験例および実施例により、本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Hereinafter, although a test example and an Example demonstrate this invention more concretely, this invention is not limited to these.
試験例１．セサミン類の鎮痛作用
セサミン類の鎮痛作用に関する報告はない。そこで、セサミン類の鎮痛作用について検討した。
Test Example 1 There is no report about the analgesic action of sesamin. Therefore, the analgesic action of sesamin was examined.
鎮痛作用試験としては、Moonらの酢酸Writhing試験（Biol. Pharm. Bull. (2005)）を一部改変した方法で行った。具体的な試験方法は以下のとおりである。Wistar系雄性ラット（５週齢）を日本クレア社より購入し、１週間試験環境で馴化させた後、順調な発育を示した動物を試験に供した。酢酸Writhing試験３日前にラットを各群６匹からなる３群に分け、対照群にはオリブ油を５ml/kgの用量で、残り２群にはセサミン類（セサミン／エピセサミン混合物；セサミン：エピセサミン（重量比）＝５：５）をそれぞれ５０、１００mg/kgの用量でオリブ油に溶解し、ゾンデを用いて経口投与した。続いて試験２日前にも同様に投与を行い、さらに試験前日には朝、夕方の２回、つまり合計で４回投与を行った。試験当日に、前日夜から一晩絶食させたラットに生理食塩水を５ml/kgで経口投与し、その１時間後に酢酸を１％含む生理食塩水を１ml/１７０gで腹腔内へ投与して、投与直後から３０分間のWrithing回数を計測した。 As an analgesic effect test, Moon et al.'S Writhing acetate test (Biol. Pharm. Bull. (2005)) was partially modified. The specific test method is as follows. Wistar male rats (5 weeks old) were purchased from CLEA Japan, and acclimated in the test environment for 1 week, and then animals that showed normal growth were subjected to the test. Three days before the Writhing Acetate test, rats were divided into 3 groups of 6 animals each, olive oil was given at a dose of 5 ml / kg in the control group, and the remaining 2 groups were sesamin (sesamin / episesamin mixture; sesamin: episesamin ( (Weight ratio) = 5: 5) was dissolved in olive oil at doses of 50 and 100 mg / kg, respectively, and orally administered using a sonde. Subsequently, the same administration was carried out 2 days before the test, and further, the administration was carried out twice in the morning and evening, that is, a total of 4 administrations on the day before the test. On the day of the test, the rats fasted overnight from the previous day were orally administered with physiological saline at 5 ml / kg, and 1 hour later, physiological saline containing 1% acetic acid was intraperitoneally administered at 1 ml / 170 g, The number of writings for 30 minutes was measured immediately after administration.
その結果を図１に示す。セサミン類投与群（Sesamin50mg,Sesamin100mg）では対照群（Olive）に比べ、若干Writhing回数が増加する傾向が見られ、セサミン類は酢酸Writhing試験において鎮痛作用を持たないことが明らかとなった。 The result is shown in FIG. In the sesamin administration group (Sesamin 50 mg, Sesamin 100 mg), the Writhing frequency tended to increase slightly compared to the control group (Olive), and it was revealed that sesamin did not have analgesic action in the acetic acid Writhing test.
実施例１．リボフラビン（ビタミンＢ 2 ）とセサミン類による鎮痛作用（１）
セサミン類によるリボフラビン（ビタミンＢ2）の鎮痛作用の向上を検証した。Wistar系雄性ラット（７週齢）を日本クレア社より購入し、１週間試験環境で馴化させた後、順調な発育を示した動物を試験に供した。酢酸Writhing試験３日前にラットを各群６匹からなる４群に分け、そのうち２群にはオリブ油を５ml/kgで、残り２群には試験例１と同じセサミン類をそれぞれ５０、１００mg/kgの用量でオリブ油（５ml/kg）に溶解し、ゾンデを用いて経口投与し、試験例１と同様に合計４回投与を行った。試験当日に、前日夜から一晩絶食させたラットに、対照群には生理食塩水を５ml/kgで、残り３群にはビタミンＢ2（リン酸リボフラビンナトリウム；ナカライテスク社）をリボフラビン当量として３０mg/kgの用量となるよう生理食塩水に溶解して経口投与し、試験例１に準じWrithing回数を計測した。
Example 1. Analgesic action by riboflavin (vitamin B 2 ) and sesamin (1)
The improvement of the analgesic action of riboflavin (vitamin B 2 ) by sesamin was verified. Wistar male rats (7 weeks old) were purchased from CLEA Japan, and acclimated in the test environment for 1 week, and then animals that showed normal growth were subjected to the test. Three days before the Writhing Acetate test, rats were divided into 4 groups consisting of 6 animals each, 2 of which were 5 ml / kg of olive oil, and the remaining 2 groups were the same sesamin compounds as in Test Example 1, 50 and 100 mg / kg, respectively. It was dissolved in olive oil (5 ml / kg) at a dose of kg and orally administered using a sonde. On the day of the test, rats fasted overnight from the previous day were given 5 ml / kg of saline for the control group and vitamin B 2 (riboflavin sodium phosphate; Nacalai Tesque) for the remaining 3 groups as riboflavin equivalents. It was dissolved in physiological saline and orally administered so as to obtain a dose of 30 mg / kg, and the number of Writhing was measured according to Test Example 1.
その結果を図２に示す。対照群（Olive+Saline）のWrithing回数に対し、ビタミンＢ2単独群（Olive+VB2）では低下する傾向を示し、ビタミンＢ2による鎮痛作用が確認された。このビタミンＢ2単独群（Olive+VB2）と比べ、セサミン類とビタミンＢ2の組合せ群（Sesamin50mg+VB2,Swsamin100mg+VB2）では、セサミン類１００mg/kg、５０mg/kgのいずれにおいてもWrithing回数が減少した。セサミン類と組み合わせることでビタミンＢ2の鎮痛作用が増強されることが明らかとなった。 The result is shown in FIG. The vitamin B 2 alone group (Olive + VB2) showed a tendency to decrease with respect to the Writhing frequency of the control group (Olive + Saline), and the analgesic action by vitamin B 2 was confirmed. Compared with this vitamin B 2 alone group (Olive + VB2), the combination group of sesamin and vitamin B 2 (Sesamin 50mg + VB2, Swsamin100mg + VB2) has the number of writhing in both sesamin 100mg / kg and 50mg / kg. Diminished. It became clear that the analgesic action of vitamin B 2 was enhanced by combining with sesamin.
実施例２．リボフラビン（ビタミンＢ 2 ）とセサミン類による鎮痛作用（２）
実施例１の再現性を確認した。Wistar系雄性ラット（５週齢）を日本クレア社より購入し、１週間試験環境で馴化させた後、順調な発育を示した動物を試験に供した。酢酸Writhing試験３日前にラットを各群１０〜１８匹からなる３群に分け、そのうち２群（１群、２群）にはオリブ油を５ml/kgで、残り２群（３群、４群）には実施例１と同じセサミン類を１００mg/kgの用量でオリブ油に溶解し、ゾンデを用いて経口投与し、実施例１と同様に合計４回投与を行った。試験当日に、前日夜から一晩絶食させたラットに、４群のうち２群（１群、３群）には生理食塩水を５ml/kgで、残り２群（２群、４群）にはビタミンＢ2（リン酸リボフラビンナトリウム；ナカライテスク社）をリボフラビン当量として３０mg/kgの用量となるよう生理食塩水に溶解して経口投与し、試験例１に準じWrithing回数を計測した。
Example 2 Analgesic action by riboflavin (vitamin B 2 ) and sesamin (2)
The reproducibility of Example 1 was confirmed. Wistar male rats (5 weeks old) were purchased from CLEA Japan, and acclimated in the test environment for 1 week, and then animals that showed normal growth were subjected to the test. Three days before the Writhing Acetate test, the rats were divided into 3 groups consisting of 10 to 18 animals in each group, of which 2 groups (1 group, 2 groups) were 5 ml / kg of olive oil and the remaining 2 groups (3 groups, 4 groups) ), The same sesamin as in Example 1 was dissolved in olive oil at a dose of 100 mg / kg, and was orally administered using a sonde, and a total of 4 administrations were performed as in Example 1. On the day of the test, the rats fasted overnight from the night before the test were given 5 ml / kg of physiological saline in 2 groups (1 group, 3 groups) of 4 groups, and the remaining 2 groups (2 groups, 4 groups). Was dissolved in physiological saline so that vitamin B 2 (sodium riboflavin phosphate; Nacalai Tesque) was equivalent to riboflavin at a dose of 30 mg / kg was orally administered, and the number of Writhing was measured according to Test Example 1.
その結果を図３に示す。対照群（Olive+Saline）のWrithing回数に対し、ビタミンＢ2単独群（Olive+VB2）では減少傾向（抑制率10.5%）が見られたが、セサミン類単独群（Sesamin+Saline）については試験例１と同様に鎮痛作用は確認されなかった。しかし、ビタミンＢ2とセサミン類との組合せ群（Sesamin+VB2）では大きく減少（抑制率26.6%）しており、ビタミンＢ2とセサミン類とによる相乗的な鎮痛効果が確認できた（Tukey多重比較検定の結果、ビタミンＢ２とセサミン類との組合せ群と対照群との間でｐ＜０．０５、セサミン類単独群との間でｐ＜０．０１であった）。 The result is shown in FIG. The number of writhing in the control group (Olive + Saline) decreased in the vitamin B 2 alone group (Olive + VB2) (inhibition rate 10.5%), but the sesamin alone group (Sesamin + Saline) was tested. As in Example 1, no analgesic action was confirmed. However, in the combination group of vitamin B 2 and sesamin (Sesamin + VB2), it was greatly reduced (suppression rate 26.6%), and the synergistic analgesic effect by vitamin B 2 and sesamin was confirmed (Tukey multiple) results of the comparison test, p <0.05 between the control group combination group of vitamin B 2 and sesamin-class compounds was p <0.01 between sesamin alone group).
実施例３．リボフラビンとセサミン類による抗疲労作用（１）
被験物質となるリボフラビンおよびセサミン類は、いずれも実施例１と同様のもの、すなわち、セサミン／エピセサミン混合物（セサミン：エピセサミン（重量比）＝５：５）およびリボフラビン（リン酸リボフラビンナトリウム；ナカライテスク社）を用いた。
Example 3 Anti-fatigue action by riboflavin and sesamin (1)
The test substances riboflavin and sesamin are the same as in Example 1, ie, a sesamin / episesamin mixture (sesamin: episesamin (weight ratio) = 5: 5) and riboflavin (sodium riboflavin phosphate; Nacalai Tesque) ) Was used.
水浸断眠試験により、疲労に対する効果を評価した。評価は、Tanakaらの方法（Neurosience, Let.352, 159−162, 2003）を一部改変した方法で実施した。すなわち、被検動物として8週齢の雄性Balb／cマウスを用い、平均体重が均等になるように１群９匹で表１のようにマウスを７群に群分けした。表１におけるリボフラビンの値は、用いたリン酸リボフラビンナトリウムをリボフラビンとして換算した値を示している。そのうち、６群は水浸断眠ストレス群として、床敷（ペーパーチップ）のかわりに水温23℃の水道水を水深7mmになるように飼育ケージに入れて飼育することにより、マウスを水浸断眠させた。2日間の水浸断眠中にそれぞれの被検サンプルを1日1回、2日間強制経口投与した。被検サンプルのうち、セサミン類はオリーブオイルに、リボフラビンは蒸留水にそれぞれ溶解した。投与順序はリボフラビンは、セサミン類の順とし、対照として蒸留水、オリーブオイルを強制経口投与した。 The effect on fatigue was evaluated by a water immersion sleep sleep test. Evaluation was performed by a method obtained by partially modifying Tanaka et al.'S method (Neurosience, Let. 352, 159-162, 2003). That is, 8 weeks old male Balb / c mice were used as test animals, and the mice were divided into 7 groups as shown in Table 1 with 9 mice per group so that the average body weight was equal. The value of riboflavin in Table 1 indicates a value obtained by converting the riboflavin sodium phosphate used as riboflavin. Of these, 6 groups were water-soaked sleep stress groups, and instead of using a floor covering (paper chip), tap water with a water temperature of 23 ° C was kept in a breeding cage to a depth of 7 mm, and mice were soaked. Made me sleep. Each test sample was orally administered by gavage once a day for 2 days during water immersion sleep for 2 days. Among the test samples, sesamin was dissolved in olive oil and riboflavin was dissolved in distilled water. The order of administration was riboflavin in the order of sesamins, and distilled water and olive oil were forcibly administered orally as controls.
水浸飼育2日後、マウスの尾に体重の8％相当の重りをつけて遊泳させ、10秒以上水没するまでの時間を測定した。水浸飼育群（水浸断眠ストレス群）のマウスが通常飼育群のマウスよりも遊泳時間が短縮するが、被検サンプル投与群マウスによって、遊泳時間の短縮をどれだけ抑制できるかにより、疲労に対する効果を判定した。 Two days after the submerged breeding, the mouse tail was allowed to swim with a weight equivalent to 8% of the body weight, and the time until submerged for 10 seconds or more was measured. Although the swimming time of the mice in the water-immersed group (water-damaged sleep stress group) is shorter than that of the mice in the normal-rearing group, depending on how much the shortening of the swimming time can be suppressed by the mice administered with the test sample, fatigue The effect on was determined.
結果を図４に示す。図より明らかなとおり、水浸飼育対照群の遊泳時間は、通常飼育対照群にくらべて短縮した。一方、セサミンやリボフラビンを投与した群は、それぞれ遊泳時間の短縮が抑制されたが、それらを同時に投与することで相乗的にその効果が増強された。 The results are shown in FIG. As is clear from the figure, the swimming time of the submerged control group was shorter than that of the normal control group. On the other hand, in the group to which sesamin or riboflavin was administered, the shortening of swimming time was suppressed, but the effect was synergistically enhanced by simultaneously administering them.
実施例４．リボフラビンとセサミン類とによる抗疲労作用（２）
表２のように６群にマウスを群分けしたこと以外は、実施例３と同様にして、リボフラビンとセサミン類による抗疲労作用を測定した。表２におけるリボフラビンの値は、用いたリン酸リボフラビンナトリウムをリボフラビンとして換算した値を示している。
Example 4 Anti-fatigue action by riboflavin and sesamin (2)
The anti-fatigue action by riboflavin and sesamin was measured in the same manner as in Example 3 except that mice were divided into 6 groups as shown in Table 2. The value of riboflavin in Table 2 indicates the value obtained by converting the riboflavin sodium phosphate used as riboflavin.
結果を図５に示す。図より明らかなとおり、セサミンとリボフラビンにおける相乗効果は、セサミンが50mg/kg、リボフラビンが10mg/kgの場合は、発揮されなかった。相乗効果を期待する場合には、リボフラビンとして換算したリボフラビンの総量を１として、セサミン類の総量が重量比で５．０より小さい必要があることが示唆された。 The results are shown in FIG. As is clear from the figure, the synergistic effect between sesamin and riboflavin was not exhibited when sesamin was 50 mg / kg and riboflavin was 10 mg / kg. In the case of expecting a synergistic effect, it was suggested that the total amount of sesamins should be smaller than 5.0 by weight, with the total amount of riboflavin converted as riboflavin being 1.
実施例５．製剤例
（製剤例１）顆粒剤
セサミン ０.０１ｇ
ビタミンＢ2 ０.０１ｇ
酢酸トコフェロール ０.２５ｇ
無水ケイ酸 ２０.５ｇ
トウモロコシデンプン １７９.０ｇ
以上の粉体を均一に混合した後に１０％ハイドロキシプロピルセルロース・エタノール溶液１００ｍｌを加え、常法通り練和し、押し出し、乾燥して顆粒剤を得た。
Embodiment 5 FIG. Formulation Example (Formulation Example 1) Granules Sesamin 0.01g
Vitamin B 2 0.01g
0.25 g of tocopherol acetate
Silica anhydride 20.5g
Corn starch 179.0g
After uniformly mixing the above powder, 100 ml of 10% hydroxypropylcellulose / ethanol solution was added, kneaded as usual, extruded and dried to obtain granules.
（製剤例２）カプセル剤
ゼラチン ６０.０％
グリセリン ３０.０％
パラオキシ安息香酸メチル ０.１５％
パラオキシ安息香酸プロピル ０.５１％
水 適量
上記成分からなるソフトカプセル剤皮の中に、以下に示す組成物を常法により充填し、１粒２００ｍｇのソフトカプセルを得た。
(Formulation Example 2) Capsule Gelatin 60.0%
Glycerin 30.0%
Methyl paraoxybenzoate 0.15%
Propyl paraoxybenzoate 0.51%
Water Appropriate amount The following composition was filled in a soft capsule skin made of the above-mentioned components by a conventional method to obtain 200 mg soft capsules.
セサミン １０.０ｍｇ
ビタミンＢ２ １.０ｍｇ
グリセリン脂肪酸エステル １５.０ｍｇ
ミツロウ １５.０ｍｇ
小麦胚芽油 ２５０ｍｇ
（製剤例３）錠剤
セサミン ０.０１ｇ
ビタミンＢ２ ０.１ｇ
デンプン ２８２ｇ
ショ糖脂肪酸エステル ９.０ｇ
酸化ケイ素 ９.０ｇ
これらを混合し、単発式打錠機にて打錠して径９ｍｍ、重量３００ｍｇの錠剤を製造した。
Sesamin 10.0mg
Vitamin B 2 1.0mg
Glycerin fatty acid ester 15.0mg
Beeswax 15.0mg
Wheat germ oil 250mg
(Formulation Example 3) Tablet Sesamin 0.01g
Vitamin B 2 0.1g
282 g starch
Sucrose fatty acid ester 9.0g
9.0g of silicon oxide
These were mixed and tableted with a single-punch tableting machine to produce tablets with a diameter of 9 mm and a weight of 300 mg.
（製剤例４）ドリンク剤
呈味： ＤＬ−酒石酸ナトリウム ０．１ｇ
コハク酸 ０．００９ｇ
甘味： 液糖 ８００ｇ
酸味： クエン酸 １２ｇ
ビタミン：ビタミンＣ １０ｇ
セサミン １ｇ
ビタミンＢ2 ３ｇ
ビタミンＥ ３ｇ
シクロデキストリン ５ｇ
香料 １５ｍｌ
塩化カリウム １ｇ
硫酸マグネシウム ０．５ｇ
上記成分を配合し、水を加えて１０リットルとした。このドリンク剤は、１回あたり約１００ｍｌを飲用する。
(Formulation example 4) Drink agent Taste: DL-sodium tartrate 0.1 g
0.009 g of succinic acid
Sweetness: 800g liquid sugar
Acidity: Citric acid 12g
Vitamins: Vitamin C 10g
Sesamin 1g
Vitamin B 2 3g
Vitamin E 3g
Cyclodextrin 5g
Fragrance 15ml
1g potassium chloride
Magnesium sulfate 0.5g
The above ingredients were blended and water was added to make 10 liters. About 100ml of this drink is drunk.
（製剤例５）錠剤
ビタミンＢ2 ０.１ｇ
デンプン ２８０ｇ
ヒドロピシプロピルセルロース ２．０ｇ
無水ケイ素 １０.０ｇ
これらを混合し、単発式打錠機にて打錠して経8mm、重量250mgの錠剤を製造した。
(Formulation Example 5) Tablet Vitamin B 2 0.1 g
280g starch
Hydropicypropylcellulose 2.0g
Anhydrous silicon 10.0g
These were mixed and tableted with a single-punch tableting machine to produce tablets with a length of 8 mm and a weight of 250 mg.
（製剤例６）ドリンク剤
果糖ブドウ糖液糖 １.１kｇ
レモン果汁 ４０g
クエン酸 ５ｇ
ビタミンＢ２ ０．２ｇ
カフェイン ５ｇ
シクロデキストリン ５ｇ
香料 ５g
上記成分を配合し、水を加えて１０リットルとした。このドリンク剤は、１回あたり約１００ｍｌを飲用する。
(Formulation example 6) Drink agent Fructose glucose liquid sugar 1.1 kg
Lemon juice 40g
Citric acid 5g
Vitamin B 2 0.2g
Caffeine 5g
Cyclodextrin 5g
Fragrance 5g
The above ingredients were blended and water was added to make 10 liters. About 100ml of this drink is drunk.
本発明のリボフラビンとセサミン類とを含む組成物は、リボフラビンの持つ生理活性、例えば鎮痛作用や抗疲労作用がセサミン類の併用摂取により相乗的に発揮されるという効果を有するものであり、ヒトや動物等に対して安全で、したがって、本発明は、継続摂取が可能である。 The composition comprising riboflavin and sesamin of the present invention has the effect that the physiological activity of riboflavin, such as analgesic action and anti-fatigue action, is synergistically exhibited by the combined use of sesamin. It is safe for animals and the like, and therefore the present invention can be continuously ingested.
Claims (6)
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| EP (2) | EP1997496B1 (en) |
| JP (2) | JP5430927B2 (en) |
| KR (1) | KR101451438B1 (en) |
| CN (1) | CN101410115B (en) |
| AU (1) | AU2007237685B2 (en) |
| CA (1) | CA2645833C (en) |
| HK (2) | HK1126663A1 (en) |
| MY (1) | MY163134A (en) |
| SG (1) | SG170120A1 (en) |
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| SG179481A1 (en) * | 2007-03-15 | 2012-04-27 | Suntory Holdings Ltd | Anti-fatigue agent |
| JP5794761B2 (en) * | 2007-09-19 | 2015-10-14 | サントリーホールディングス株式会社 | Anti-fatigue agent containing sesamin and vitamin E |
| KR101528380B1 (en) * | 2007-09-19 | 2015-06-11 | 산토리 홀딩스 가부시키가이샤 | Composition comprising sesamin component and arachidonic acid component |
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| WO2016152846A1 (en) * | 2015-03-23 | 2016-09-29 | サントリーホールディングス株式会社 | Composition for improving circadian rhythm |
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- 2007-03-15 EP EP07738720.7A patent/EP1997496B1/en not_active Not-in-force
- 2007-03-15 US US12/282,707 patent/US20090054443A1/en not_active Abandoned
- 2007-03-15 EP EP14184312.8A patent/EP2826481A1/en not_active Withdrawn
- 2007-03-15 JP JP2008510789A patent/JP5430927B2/en active Active
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- 2007-03-15 WO PCT/JP2007/055270 patent/WO2007119378A1/en active Application Filing
- 2007-03-15 CA CA2645833A patent/CA2645833C/en active Active
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2009
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2013
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| HK1201754A1 (en) | 2015-09-11 |
| CA2645833C (en) | 2014-12-30 |
| CA2645833A1 (en) | 2007-10-25 |
| EP1997496A1 (en) | 2008-12-03 |
| MY163134A (en) | 2017-08-15 |
| AU2007237685B2 (en) | 2012-08-09 |
| TW200803865A (en) | 2008-01-16 |
| JPWO2007119378A1 (en) | 2009-08-27 |
| HK1126663A1 (en) | 2009-09-11 |
| CN101410115A (en) | 2009-04-15 |
| EP1997496B1 (en) | 2015-07-29 |
| US20150080407A1 (en) | 2015-03-19 |
| EP2826481A1 (en) | 2015-01-21 |
| JP5430927B2 (en) | 2014-03-05 |
| SG170120A1 (en) | 2011-04-29 |
| WO2007119378A1 (en) | 2007-10-25 |
| CN101410115B (en) | 2012-01-04 |
| KR20080110814A (en) | 2008-12-19 |
| US20090054443A1 (en) | 2009-02-26 |
| EP1997496A4 (en) | 2012-05-16 |
| KR101451438B1 (en) | 2014-10-15 |
| TWI407963B (en) | 2013-09-11 |
| AU2007237685A1 (en) | 2007-10-25 |
| JP2014040463A (en) | 2014-03-06 |
| US9895375B2 (en) | 2018-02-20 |
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